Dental Mesenchymal Stem Cell Secretome: An Intriguing Approach for Neuroprotection and Neuroregeneration

Mesenchymal stem cells (MSCs) are known for their beneficial effects and regenerative potential. In particular, dental-derived MSCs have the advantage of easier accessibility and a non-invasive isolation method. Moreover, thanks to their neural crest origin, dental MSCs seem to have a more prominent neuroregenerative potential. Indeed, in basal conditions they also express neuronal markers. However, it is now well known that the beneficial actions of MSCs depend, at least in part, on their secretome, referring to all the bioactive molecules released in the conditioned medium (CM) or in extracellular vesicles (EVs). In this review we focus on the applications of the secretome derived from dental MSCs for neuroregeneration and neuroprotection. The secretomes of different dental MSCs have been tested for their effects for neuroregenerative purposes, and the secretomes of dental pulp stem cells and stem cells from human exfoliated deciduous teeth are the most studied. Both the CM and EVs obtained from dental MSCs showed that they are able to promote neurite outgrowth and neuroprotective effects. Interestingly, dental-derived MSC secretome showed stronger neuroregenerative and neuroprotective effects compared to that obtained from other MSC sources. For these reasons, the secretome obtained from dental MSCs may represent a promising approach for neuroprotective treatments.

Hepatocyte Growth Factor-Preconditioned Neural Progenitor Cells Attenuate Astrocyte Reactivity and Promote Neurite Outgrowth

The astroglial scar is a defining hallmark of secondary pathology following central nervous system (CNS) injury that, despite its role in limiting tissue damage, presents a significant barrier to neuroregeneration. Neural progenitor cell (NPC) therapies for tissue repair and regeneration have demonstrated favorable outcomes, the effects of which are ascribed not only to direct cell replacement but trophic support. Cytokines and growth factors secreted by NPCs aid in modifying the inhibitory and cytotoxic post-injury microenvironment. In an effort to harness and enhance the reparative potential of NPC secretome, we utilized the multifunctional and pro-regenerative cytokine, hepatocyte growth factor (HGF), as a cellular preconditioning agent. We first demonstrated the capacity of HGF to promote NPC survival in the presence of oxidative stress. We then assessed the capacity of this modified conditioned media (CM) to attenuate astrocyte reactivity and promote neurite outgrowth in vitro. HGF pre-conditioned NPCs demonstrated significantly increased levels of tissue inhibitor of metalloproteinases-1 and reduced vascular endothelial growth factor compared to untreated NPCs. In reactive astrocytes, HGF-enhanced NPC-CM effectively reduced glial fibrillary acidic protein (GFAP) expression and chondroitin sulfate proteoglycan deposition to a greater extent than either treatment alone, and enhanced neurite outgrowth of co-cultured neurons. in vivo, this combinatorial treatment strategy might enable tactical modification of the post-injury inhibitory astroglial environment to one that is more conducive to regeneration and functional recovery. These findings have important translational implications for the optimization of current cell-based therapies for CNS injury.